Clinical Manifestations, Staging, and Treatment of Follicular Lymphoma

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Chapter 34 Clinical Manifestations, Staging, and Treatment of Follicular Lymphoma

John G. Gribben

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Figure 34-1 FOLLICULAR LYMPHOMA: MORPHOLOGIC AND IMMUNOPHENOTYPIC FINDINGS.

A, A low-power photomicrograph illustrates a lymph node involved by follicular lymphoma. The lymphoma cells grow in nodules or follicles that resemble the normal lymphoid follicles of a reactive lymph node. However, in the lymphomatous growth, the follicles are crowded, show back-to-back localization, and lack many of the features of their reactive counterparts. At higher power (B), the neoplastic follicles lack mantle zones and the normal polarization of small and large germinal center cells (centrocytes and centroblasts, respectively), which occurs due to the cellular response to antigenic stimulation as it sweeps thorough the follicle. The neoplastic follicles stain for the germinal center marker, BCL6 and CD10 (C); however, they overexpress BCL2 (D) as a result of the associated translocation t(14;18), involving the IgH gene and BCL2. BCL2 is not much expressed in normal germinal center B cells (E, control for comparison). Follicular lymphoma is graded by the number of large neoplastic cells (centroblasts) present among the smaller neoplastic cells (centrocytes) (F to I). The grading system is not entirely accurate, but it provides some framework for subclassifying cases morphologically. Grade 1 is 0 to 5 centroblasts per average 40x field (F); between 6 and 15 is grade 2 (G); and more than 15 is grade 3A (H). Grades 1 and 2 are now considered together. When most of the cells in the neoplastic follicles are centroblasts without centrocytes, the case is considered grade 3B (I).

Table 34-1 Initial Evaluation of Follicular Lymphoma

Physical examination with attention to peripheral nodes, abdomen

Complete blood count; evaluation of peripheral blood

Liver function tests; LDH; beta-2-microglobulin

CT scans of chest, abdomen, pelvis (PET scan if indicated)

Lymph node biopsy with review by an expert lymphoma histopathologist

Bone marrow biopsy/aspirate

Other studies as indicated

Table 34-2 Ann Arbor Staging

Stage Criteria
I Involvement of 1 lymph node (I) or 1 extralymphatic organ or site (IE)
II Involvement of 2 or more lymph nodes on same side of diaphragm (II) or localized extralymphatic organ or site and 1 or more involved lymph node on same side of diaphragm (IIE)
III Involvement of lymph nodes on both sides of diaphragm (III) or same side with localized involvement of extralymphatic site (IIIE), spleen (IIIS), or both (IIIS+E)
IV Diffuse or disseminated involvement of extralymphatic organ or tissues with or without lymph node enlargement
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Figure 34-2 PROBABILITY OF RISK FOR TRANSFORMATION OF PATIENTS WITH FOLLICULAR LYMPHOMA.

Table 34-3 Factors Having Prognostic Significance in the FLIPI* and FLIPI2†

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FLIP, Follicular lymphoma international prognostic index; HR, hazard ratio; LDH, lactate dehydrogenase, ULN, upper limit of normal.

* From Solal-Celigny P, Roy P, Colombat P, et al: Follicular lymphoma international prognostic index. Blood 104:1258, 2004.

† From Federico M, Bellei M, Marcheselli L, et al: Follicular lymphoma international prognostic index 2: A new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol 27:4555, 2009.

Table 34-4 Outcome by FLIPI2

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Data from Federico M, Bellei M, Marcheselli L, et al: Follicular lymphoma international prognostic index 2: A new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol 27:4555, 2009.

Table 34-5 Treatment Strategies for Indolent Lymphomas

LOCALIZED DISEASE

Radiotherapy

“Watch and wait”
ADVANCED-STAGE DISEASE

“Watchful waiting”

Chemotherapy

Alkylating agents

Bendamustine

Purine analogues

Combination chemotherapy

Monoclonal antibodies

Unconjugated

Conjugated—radioimmunoconjugates and immunotoxins

Chemotherapy + monoclonal antibodies (chemoimmunotherapy)

High-dose chemotherapy plus autologous/allogeneic stem cell transplantation

Reduced-intensity conditioning allogeneic transplantation

Palliative radiotherapy

Management of Follicular Lymphoma

Patients most often present with asymptomatic lymphadenopathy. The diagnosis should be made by excisional biopsy and review by an expert hematopathologist. In the absence of symptoms requiring treatment, an expectant “watch and wait” approach is the treatment of choice. While in this phase of treatment, patients should be followed every 3 to 6 months for history, physical examination, and laboratory results with radiologic restaging as clinically indicated. Once a decision to treat has been made, no clear treatment algorithm exists, and a number of treatment options are available. The treatment goal, whether palliative or potentially with curative intent, is dependent on the age and performance status of patients. Enrollment in a clinical trial should be the treatment of choice. For younger patients in whom high-dose therapy may be indicated later in their disease course, it is best to avoid profoundly myelotoxic regimens. The role of maintenance therapy in first remission using interferon-α remains controversial, and the use of rituximab maintenance therapy in first remission remains the focus of ongoing clinical trials. The choice of therapy after first relapse depends again on the goal of therapy; however, it is also dependent on the previous therapy, response, and duration of response. Autologous or allogeneic stem cell transplantation has a role to play in selected younger patients with this disease.

Table 34-6 National LymphoCare Study Survey of Current Practice for Follicular Lymphoma in the United States, 2004 to 2007

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Data from Friedberg JW, Taylor MD, Cerhan JR, et al: Follicular lymphoma in the United States: First report of the national LymphoCare study. J Clin Oncol 27:1202, 2009.

Table 34-7 Chemotherapy Regimens in Indolent Lymphomas

CVP (EVERY 21 DAYS)

• cyclophosphamide 750 mg/m2 IV on day 1

• vincristine 1.4 mg/m2, up to a maximal dose of 2 mg IV, on day 1

• prednisone 40 mg/m2 daily PO on days 1 to 5

Patients being treated with R-CVP also received 375 mg/m2 of rituximab IV on day 1 of each therapy cycle.1
CHOP (EVERY 21 DAYS)

• cyclophosphamide 750 mg/m2 IV on day 1

• hydroxydaunomycin 50 mg/m2 IV on day 1

• vincristine (Oncovin) 1.4 mg/m2, up to a maximal dose of 2 mg IV, on day 1

• prednisone 100 mg daily orally on days 1 to 5

Patients being treated with R-CHOP also received 375 mg/m2 of rituximab IV on day 1 of each therapy cycle2 or by alternate schedule.3
CNOP (EVERY 21 DAYS)

• cyclophosphamide 750 mg/m2 IV on day 1

• mitoxantrone (Novantrone) 10 mg/m2 IV on day 1

• vincristine (Oncovin) 1.4 mg/m2, up to a maximal dose of 2 mg IV, on day 1

• prednisone 50 mg/m2 daily orally on days 1 to 5

CHVP-IFN (EVERY 28 DAYS FOR 6 MONTHS, THEN EVERY 2 MONTHS FOR 6 MONTHS)4

• cyclophosphamide 600 mg/m2

• hydroxydaunomycin 25 mg/m2

• etoposide (Vepesid) 100 mg/m2 on day 1 (replaces original teniposide 60 mg/m2 on day 1)

• prednisolone 40 mg/m2 on days 1 to 5

• interferon-α-5, 3 times a week

Patients being treated with R-CHVP also received 375 mg/m2 of rituximab IV on day 1 of each therapy cycle for six cycles.

FMD (EVERY 28 DAYS)

• fludarabine 25 mg/m2 IV on days 1-3

• mitoxantrone 10 mg/m2 IV on day 1

• dexamethasone 20 mg /day PO days 1 to 5

Patients being treated with R-FMD also received 375 mg/m2 of rituximab IV on day 1 of each therapy cycle.

PROMACE-MOPP

Cycles repeated every 28 days

Day 1

• cyclophosphamide 650 mg/m2 IV

• doxorubicin 25 mg/m2 IV

• etoposide 120 mg/m2 IV

• prednisone 60 mg/m2 orally daily days 1-14

Day 8

• mechlorethamine 6 mg/m2 IV

• vincristine 1.4 mg/m2 (maximum 2 mg) IV on day 8

• procarbazine 100 mg/m2 orally daily days 8-14

Day 15

• methotrexate 500 mg/m2 IV on day 15

• leucovorin 50 mg/m2 orally every 6 hours for four doses beginning 24 hours after methotrexate

R-HYPER-CVAD (EVERY 21 DAYS)5 Cycles I, 3, 5, and 7

• rituxumab 375 mg/m2 IV on day 1

• cyclophosphamide (with mesna) 300 mg/m2 IV over 3 hours every 12 hours on days 2-4 (total six doses)

• vincristine 1.4 mg/m2 (maximum 2 mg) IV on days 5 and 12

• doxorubicin (Adriamycin) 16.6 mg/m2 IV by continuous infusion on days 5-7

• dexamethasone 40 mg/day PO/IV on days 2-5 and days 12-15

Cycles 2,4, 6, and 8

• rituxumab 375 mg/m2 IV on day 1

• methotrexate 200 mg/m2 IV over 2 hours, followed by 800 mg/m2 IV continuous infusion over 22 hours on day 2

• leucovorin 50 mg PO starting 12 hours after completion of methotrexate infusion, followed by 15 mg PO every 6 hours for 8 dosed until the methotrexate level is less than 0.1 µM/L

• cytarabine 3000 mg/m2 IV over 2 hours every 12 hours on days 3 and 4 (4 doses total)

References

1 Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005;105:1417.

2 Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2005;106:3725.

3 Czuczman MS, Grillo-Lopez AJ, White CA, et al. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol. 1999;17:268.

4 Sebban C, Mounier N, Brousse N, et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d’Etude des Lymphomes de l’Adulte (GELA). Blood. 2006;108:2540.

5 Romaguera JE, Fayad L, Rodriguez MA, et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005;23:7013.

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